Included as part of the PRECAUTIONS section.
Rhabdomyolysis with acute renal
failure secondary to myoglobinuria have been reported with LESCOL/LESCOL XL and
other drugs in this class.
LESCOL/LESCOL XL should be
prescribed with caution in patients with predisposing factors for myopathy.
These factors include advanced age ( > 65 years), renal impairment, and inadequately
The risk of myopathy and/or
rhabdomyolysis with statins is increased with concurrent therapy with
cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with
LESCOL/LESCOL XL together with niacin. Isolated cases of myopathy have been
reported during post-marketing experience with concomitant administration of
LESCOL/LESCOL XL and colchicine. No information is available on the pharmacokinetic
interaction between LESCOL/LESCOL XL and colchicine.
Uncomplicated myalgia has also
been reported in LESCOL-treated patients [see ADVERSE REACTIONS]. In
clinical trials, uncomplicated myalgia has been observed infrequently in
patients treated with LESCOL at rates indistinguishable from placebo. Myopathy,
defined as muscle aching or muscle weakness in conjunction with increases in
CPK values to greater than 10 times the upper limit of normal, was < 0.1% in
fluvastatin clinical trials. Myopathy should be considered in any patient with
diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of
CPK. Patients should be advised to report promptly unexplained muscle pain,
tenderness or weakness, particularly if accompanied by malaise or fever.
LESCOL/LESCOL XL therapy should be
discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or
suspected. LESCOL/LESCOL XL therapy should also be temporarily withheld in any
patient experiencing an acute or serious condition predisposing to the
development of renal failure secondary to rhabdomyolysis, e.g., sepsis;
hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte
disorders; or uncontrolled epilepsy.
Increases in serum transaminases
(aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase, or alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase) have been
reported with HMG-CoA reductase inhibitors, including LESCOL/LESCOL XL. In most
cases, the elevations were transient and resolved or improved on continued
therapy or after a brief interruption in therapy.
Approximately 1.1% of patients
treated with LESCOL capsules in worldwide trials developed dose-related,
persistent elevations of serum transaminase levels to more than 3 times the
upper limit of normal. Fourteen of these patients (0.6%) were discontinued from
therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had
persistent transaminase elevations with an average LESCOL exposure of
approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The
majority of patients with these abnormal biochemical findings were
In a pooled analysis of all
placebo-controlled studies in which LESCOL capsules were used, persistent
transaminase elevations ( > 3 times the upper limit of normal [ULN] on two
consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients
treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily)
LESCOL capsules, respectively. Ninety-one percent of the cases of persistent
liver function test abnormalities (20 of 22 patients) occurred within 12 weeks
of therapy and in all patients with persistent liver function test abnormalities
there was an abnormal liver function test present at baseline or by Week 8.
In the pooled analysis of the
24-week controlled trials, persistent transaminase elevation occurred in 1.9%,
1.8% and 4.9% of patients treated with LESCOL XL 80 mg, LESCOL 40 mg and LESCOL
40 mg twice daily, respectively. In 13 of 16 patients treated with LESCOL XL
the abnormality occurred within 12 weeks of initiation of treatment with LESCOL
XL 80 mg.
It is recommended that liver
enzyme tests be performed prior to the initiation of LESCOL/LESCOL XL, and if
signs or symptoms of liver injury occur.
There have been rare postmarketing
reports of fatal and non-fatal hepatic failure in patients taking statins,
including fluvastatin. If serious liver injury with clinical symptoms and/or
hyperbilirubinemia or jaundice occurs during treatment with LESCOL/LESCOL XL,
promptly interrupt therapy. If an alternate etiology is not found do not
restart LESCOL/LESCOL XL.
In very rare cases, possibly
drug-related hepatitis was observed that resolved upon discontinuation of
treatment.1 Active liver disease or unexplained serum transaminase
elevations are contraindications to the use of LESCOL and LESCOL XL [see CONTRAINDICATIONS. Caution should be exercised when LESCOL
is administered to patients with a history of liver disease or heavy alcohol
ingestion [see CLINICAL PHARMACOLOGY]. Such patients should be closely
Increases in HbA1c and fasting
serum glucose levels have been reported with HMG-CoA reductase inhibitors,
including LESCOL/LESCOL XL.
Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might
theoretically blunt adrenal or gonadal steroid hormone production.
LESCOL/LESCOL XL exhibited no
effect upon non-stimulated cortisol levels and demonstrated no effect upon
thyroid metabolism as assessed by measurement of thyroid stimulating hormone
(TSH). Small declines in total serum testosterone have been noted in treated
groups, but no commensurate elevation in LH occurred, suggesting that the
observation was not due to a direct effect upon testosterone production. No
effect upon FSH in males was noted. Due to the limited number of premenopausal
females studied to date, no conclusions regarding the effect of LESCOL/LESCOL
XL upon female sex hormones may be made.
Two clinical studies in patients
receiving fluvastatin at doses up to 80 mg daily for periods of 24 to 28 weeks
demonstrated no effect of treatment upon the adrenal response to ACTH
stimulation. A clinical study evaluated the effect of LESCOL at doses up to 80
mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although
the mean total testosterone response was significantly reduced (p < 0.05)
relative to baseline in the 80 mg group, it was not significant in comparison
to the changes noted in groups receiving either 40 mg of LESCOL or placebo.
Patients treated with
LESCOL/LESCOL XL who develop clinical evidence of endocrine dysfunction should
be evaluated appropriately. Caution should be exercised if a statin or other
agent used to lower cholesterol levels is administered to patients receiving
other drugs (e.g. ketoconazole, spironolactone, cimetidine) that may decrease the
levels of endogenous steroid hormones.
CNS effects, as evidenced by
decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the
following animal studies: the 18-month mouse carcinogenicity study at 50
mg/kg/day, the 6-month dog study at 36 mg/kg/day, the 6-month hamster study at
40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg),
rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose
studies was characterized (in mice) by conspicuous vacuolation in the ventral
white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema
with separation of myelinated fibers of the ventral spinal tracts and sciatic
nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal
vacuolation, was observed in the medulla of dogs that died after treatment for
5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs
when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized
by perivascular hemorrhages, edema, and mononuclear cell infiltration of
perivascular spaces, have been observed in dogs treated with other members of
this drug class. No CNS lesions have been observed after chronic treatment for
up to 2 years with fluvastatin in the mouse (at doses up to 350 mg/kg/day), rat
(up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).
Prominent bilateral posterior Y
suture lines in the ocular lens were seen in dogs after treatment with 1, 8,
and 16 mg/kg/day for 2 years.
Patient Counseling Information
Information For Patients
Patients taking LESCOL/LESCOL XL should
be advised that high cholesterol is a chronic condition and they should adhere
to their medication along with their National Cholesterol Education Program
(NCEP)-recommended diet, a regular exercise program, and periodic testing of a
fasting lipid panel to determine goal attainment.
Patients should be advised
about substances they should not take concomitantly with LESCOL/LESCOL XL [see WARNINGS AND PRECAUTIONS].
Patients should also be advised to inform other healthcare professionals
prescribing a new medication that they are taking LESCOL/LESCOL XL.
Patients starting therapy with
LESCOL/LESCOL XL should be advised of the risk of myopathy and told to report
promptly any unexplained muscle pain, tenderness or weakness, particularly if
accompanied by malaise or fever.
It is recommended that liver
enzyme tests be performed before the initiation of LESCOL/LESCOL XL and if
signs or symptoms of liver injury occur. All patients treated with
LESCOL/LESCOL XL should be advised to report promptly any symptoms that may
indicate liver injury, including fatigue, anorexia, right upper abdominal
discomfort, dark urine or jaundice.
Women of childbearing age should
be advised to use an effective method of birth control to prevent pregnancy
while using LESCOL/LESCOL XL. Discuss future pregnancy plans with your
patients, and discuss when to stop taking LESCOL/LESCOL XL if they are trying
to conceive. Patients should be advised that if they become pregnant they
should stop taking LESCOL/LESCOL XL and call their healthcare professional.
Women who are breastfeeding should
not use LESCOL/LESCOL XL. Patients who have a lipid disorder and are
breastfeeding should be advised to discuss the options with their healthcare
Impairment of Fertility
A 2-year study was performed in
rats at dose levels of 6, 9, and 18-24 (escalated after 1 year) mg/kg/day.
These treatment levels represented plasma drug levels of approximately 9, 13,
and 26-35 times the mean human plasma drug concentration after a 40 mg oral
dose. A low incidence of forestomach squamous papillomas and 1 carcinoma of the
forestomach at the 24 mg/kg/day dose level was considered to reflect the
prolonged hyperplasia induced by direct contact exposure to fluvastatin sodium
rather than to a systemic effect of the drug. In addition, an increased
incidence of thyroid follicular cell adenomas and carcinomas was recorded for
males treated with 18-24 mg/kg/day. The increased incidence of thyroid
follicular cell neoplasm in male rats with fluvastatin sodium appears to be
consistent with findings from other HMG-CoA reductase inhibitors. In contrast
to other HMG-CoA reductase inhibitors, no hepatic adenomas or carcinomas were
The carcinogenicity study
conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in
rats, a statistically significant increase in forestomach squamous cell
papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day.
These treatment levels represented plasma drug levels of approximately 0.05, 2,
and 7 times the mean human plasma drug concentration after a 40 mg oral dose.
No evidence of mutagenicity was
observed in vitro, with or without rat-liver metabolic activation, in the
following studies: microbial mutagen tests using mutant strains of Salmonella
typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3
cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal
aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In
addition, there was no evidence of mutagenicity in vivo in either a rat or
mouse micronucleus test.
In a study in rats at dose levels
for females of 0.6, 2 and 6 mg/kg/day and at dose levels for males of 2, 10 and
20 mg/kg/day, fluvastatin sodium had no adverse effects on the fertility or
Seminal vesicles and testes were
small in hamsters treated for 3 months at 20 mg/kg/day (approximately three
times the 40 mg human daily dose based on surface area, mg/m²). There was
tubular degeneration and aspermatogenesis in testes as well as vesiculitis of
seminal vesicles. Vesiculitis of seminal vesicles and edema of the testes were
also seen in rats treated for 2 years at 18 mg/kg/day (approximately 4 times
the human Cmax achieved with a 40 mg daily dose).
Fluvastatin sodium produced delays
in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at
doses of 10 mg/kg/day. Malaligned thoracic vertebrae were seen in rats at 36
mg/kg, a dose that produced maternal toxicity. These doses resulted in 2 times
(rat at 12 mg/kg) or 5 times (rabbit at 10 mg/kg) the 40 mg human exposure
based on mg/m2 surface area. A study in which female rats were dosed
during the third trimester at 12 and 24 mg/kg/day resulted in maternal
mortality at or near term and postpartum. In addition, fetal and neonatal
lethality were apparent. No effects on the dam or fetus occurred at 2
mg/kg/day. A second study at levels of 2, 6, 12 and 24 mg/kg/day confirmed the
findings in the first study with neonatal mortality beginning at 6 mg/kg. A
modified Segment III study was performed at dose levels of 12 or 24 mg/kg/day
with or without the presence of concurrent supplementation with mevalonic acid,
a product of HMG-CoA reductase which is essential for cholesterol biosynthesis.
The concurrent administration of mevalonic acid completely prevented the
maternal and neonatal mortality but did not prevent low body weights in pups at
24 mg/kg on days 0 and 7 postpartum.
Use In Specific Populations
Pregnancy Category X
LESCOL/LESCOL XL is
contraindicated in women who are or may become pregnant [see CONTRAINDICATIONS].
Lipid lowering drugs are
contraindicated during pregnancy, because cholesterol and cholesterol
derivatives are needed for normal fetal development. Serum cholesterol and
triglycerides increase during normal pregnancy. Atherosclerosis is a chronic
process, and discontinuation of lipid-lowering drugs during pregnancy should
have little impact on long-term outcomes of primary hypercholesterolemia
There are no adequate and
well-controlled studies of use with LESCOL/LESCOL XL during pregnancy. Rare
reports of congenital anomalies have been received following intrauterine
exposure to other statins. In a review2 of about 100 prospectively
followed pregnancies in women exposed to other statins, the incidences of
congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did
not exceed the rate expected in the general population. The number of cases is
adequate only to exclude a 3-to 4-fold increase in congenital anomalies over
background incidence. In 89% of prospectively followed pregnancies, drug
treatment was initiated prior to pregnancy and was discontinued at some point
in the first trimester when pregnancy was identified.
Teratology studies with
fluvastatin in rats and rabbits showed maternal toxicity at high dose levels,
but there was no evidence of embryotoxic or teratogenic potential [see Non-Clinical
LESCOL or LESCOL XL should be
administered to women of child-bearing potential only when such patients are
highly unlikely to conceive and have been informed of the potential hazards. If
a woman becomes pregnant while taking LESCOL or LESCOL XL, the drug should be
discontinued and the patient advised again as to the potential hazards to the
Based on animal data, fluvastatin
is present in breast milk in a 2:1 ratio (milk:plasma). Because of the
potential for serious adverse reactions in nursing infants, nursing women
should not take LESCOL or LESCOL XL [see CONTRAINDICATIONS].
The safety and efficacy of LESCOL
and LESCOL XL in children and adolescent patients 9-16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label,
uncontrolled clinical trials for a duration of two years. The most common
adverse events observed were influenza and infections. In these limited
uncontrolled studies, there was no detectable effect on growth or sexual
maturation in the adolescent boys or on menstrual cycle length in girls [see
Clinical Studies, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION].
Adolescent females should be counseled on appropriate contraceptive methods while
on LESCOL therapy [see CONTRAINDICATIONS].
Fluvastatin exposures were not
significantly different between the nonelderly and elderly populations (age ≥ 65 years) [see CLINICAL
PHARMACOLOGY]. Since advanced age ( > 65
years) is a predisposing factor for myopathy, LESCOL/LESCOL XL should be
prescribed with caution in the elderly.
LESCOL and LESCOL XL are
contraindicated in patients with active liver disease or unexplained,
persistent elevations in serum transaminases [see CLINICAL PHARMACOLOGY].
Dose adjustments for mild to
moderate renal impairment are not necessary. Fluvastatin has not been studied
at doses greater than 40 mg in patients with severe renal impairment; therefore
caution should be exercised when treating such patients at higher doses [see CLINICAL
1. National Cholesterol Education Program (NCEP): Highlights
of the Report of the Expert Panel on Blood Cholesterol Levels in Children and
Adolescents. Pediatrics. 89(3):495-501.1992.
2. Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson,
W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy, Reproductive Toxicology, 10(6): 439-446, 1996.